{"id":3802,"date":"2011-04-09T16:26:55","date_gmt":"2011-04-09T16:26:55","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=3802"},"modified":"2019-11-29T10:22:03","modified_gmt":"2019-11-29T10:22:03","slug":"why-are-%ce%b1-helices-in-proteins-mostly-right-handed","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=3802","title":{"rendered":"Why are \u03b1-helices in proteins mostly right handed?"},"content":{"rendered":"
\n

Understanding why and how proteins fold continues to be a grand challenge<\/em> in science. I have described<\/a> how Wrinch in 1936 made a bold proposal for the mechanism, which however flew in the face of much of then known chemistry. Linus Pauling took most of the credit (and a Nobel prize) when in a famous paper[1]<\/a><\/span> in 1951 he suggested a mechanism that involved (inter alia<\/em>) the formation of what he termed \u03b1-helices. Jack Dunitz in 2001[2]<\/a><\/span> wrote a must-read article[3]<\/a><\/span> on the topic of “Pauling’s Left-handed \u03b1-helix” (it is now known to be right handed).\u00a0I thought I would revisit this famous example with a calculation of my own and here I have used the\u00a0\u03c9B97XD\/6-311G(d,p) DFT procedure[4]<\/a><\/span> to calculate some of the energy components of a small helix comprising (ala)6 <\/sub>in both left and right handed form.<\/p>\n

Firstly, it is important to note that Pauling was apparently not aware of the absolute handedness of amino acids (which are (S) in CIP terminology). This had in fact only been established<\/a> a few months before Pauling’s publication by Bijvoet[5]<\/a><\/span>,\u00a0and news of this might not have reached Pauling. So Pauling guessed (or perhaps, he had already built his models, and did not have time to reconstruct them) and his famous\u00a0\u03b1-helix diagram[1]<\/a><\/span> turned out to be the enantiomer of the real McCoy. As with DNA itself<\/a>, the helix bears a diastereomeric relationship to the chirality of the amino acids; both have to be inverted to get the proper enantiomer (which is what Pauling did). The secret that Pauling had discovered was hydrogen bonding, and particular, weak N-H…O=C interactions (Wrinch had thought it was strong covalent N-C-OH bonding instead). Of course, there are other effects at work, which include van der Waals or dispersion interactions, electrostatic effects resulting from the large dipoles in peptides (not least due to the zwitterionic character), the planarity of the peptide bond<\/a> itself, the potential for other types of hydrogen bond (e.g.<\/em> C-H…O) and entropic effects. I have split some of these down for left and right handed forms of DNA in another post<\/a>.<\/p>\n

It turns out calculating most of these effects on an even-handed basis is not that easy. Only the recent advent of dispersion-corrected DFT procedures, together with solvation algorithms that allow for accurate geometry optimisation and subsequent evaluation of free energies allows such a calculation to be performed. Hitherto, it has been mostly molecular mechanics that has been used (which itself relies on many parameters from quantum mechanics, such as atom charges, and explicitly\u00a0identifying interactions for hydrogen bonding). By returning to a quantum-mechanical model, some of these assumptions inherent in the mechanics method need not be made.<\/p>\n

We\u00a0showed in 1991[6]<\/a><\/span> that an effective solvation treatment required for the zwitterionic form of amino acids in aqueous solutions would ideally comprise not only a self-consistent-reaction-field, but also explicit water molecules as solvent. Here only the former solvation term is included, but expanding the model to include water is certainly possible. Both the zwitterionic and the neutral forms of (ala)6<\/sub> are included below, so that the effect of a large dipole on the structure and relative helical stability can be estimated. One notes that (even in a dielectric cavity corresponding to water), the extended zwitterions are high energy species. \u00a0In a protein, they of course would be stabilized by the immediate environment of the ions. The right-handed helix clearly comes out as more stable (by about 1 kcal\/mol per residue, see also[7]<\/a><\/span>\u00a0but this is not really due to either dispersion effects or entropy and must therefore arise largely from the hydrogen-bond like interactions. Ionizing the termini to form a zwitterion increases the propensity for a right handed helix slightly.<\/p>\n\n\n\n\n\n\n\n\n\n
Relative thermodynamic energies (kcal mol-1<\/sup>) of (ala)6<\/sub> \u03b1-helices<\/th>\n<\/tr>\n<\/thead>\n
System<\/th>\nTotal energy<\/th>\nDispersion<\/th>\n\u0394\u0394H298<\/sub><\/th>\n\u0394(T.\u0394S298<\/sub>)<\/th>\n\u0394\u0394G298<\/sub><\/th>\n<\/tr>\n
Left, neutral<\/td>\n0.0
<\/td>\n		0.0<\/td>\n0.0<\/td>\n0.0<\/td>\n0.0<\/a><\/td>\n<\/tr>\n
Right, neutral<\/td>\n-4.0
<\/td>\n		+0.2<\/td>\n-4.0<\/td>\n0.9<\/td>\n-4.9<\/a><\/td>\n<\/tr>\n
Left, zwitterion<\/td>\n0.0<\/td>\n0.0<\/td>\n0.0<\/td>\n0.0<\/td>\n0.0<\/a><\/td>\n<\/tr>\n
Right, zwitterion<\/td>\n-7.1<\/td>\n0.1<\/td>\n-6.3<\/td>\n1.7<\/td>\n-8.0<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Shown below are the calculated structures. The chains have (inter alia) unusual bifurcated hydrogen-bonding interactions, between one carbonyl group and two N-H groups (show as atom with halo). These are not quite the models that Linus Pauling built!<\/p>\n\n\n\n\n
\n
\"\"<\/span>

Left handed. Click for 3D<\/p><\/div><\/td>\n

\n
\"\"

Right handed. Click for 3D<\/p><\/div><\/td>\n<\/tr>\n

\n
\"\"

Left handed zwitterion. Click for 3D<\/p><\/div><\/td>\n

\n
\"\"

Right handed zwitterion. Click for 3D<\/p><\/div><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

For a more objective analysis of the interactions within the system, a QTAIM analysis is shown below.<\/p>\n\n\n\n
\n
\"\"

Left helix. Bond critical points in green. Click for 3D.<\/p><\/div><\/td>\n

\n
\"\"

Right helix. Click for 3D<\/p><\/div><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Whilst the overall conclusion is that theory agrees well with the experimental observation that peptide sequences tend to coil into right rather than left handed helices,\u00a0the reasons they do so is a little more subtle than simple model building alone can reveal.\u00a0As the AIM shows, a plethora of unusual and weaker interactions occur within these helices, a full analysis of which must await presentation elsewhere.<\/p>\n

An NCI analysis reveals strong hydrogen bonds as blue-shaded surfaces.<\/p>\n

\"\"

NCI surface. Click for 3D.<\/p><\/div>\n

References<\/h2>\n
  1. L. Pauling, R.B. Corey, and H.R. Branson, \"The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain\", Proceedings of the National Academy of Sciences<\/i>, vol. 37, pp. 205-211, 1951. https:\/\/doi.org\/10.1073\/pnas.37.4.205<\/a>\n\n<\/li>\n
  2. J.D. Dunitz, \"Pauling's Left-Handed \u03b1-Helix\", Angewandte Chemie International Edition<\/i>, vol. 40, pp. 4167-4173, 2001. https:\/\/doi.org\/10.1002\/1521-3773(20011119)40:22<4167::aid-anie4167>3.0.co;2-q<\/a>\n\n<\/li>\n
  3. https:\/\/doi.org\/<\/a>\n\n<\/li>\n
  4. K.S. Thanthiriwatte, E.G. Hohenstein, L.A. Burns, and C.D. Sherrill, \"Assessment of the Performance of DFT and DFT-D Methods for Describing Distance Dependence of Hydrogen-Bonded Interactions\", Journal of Chemical Theory and Computation<\/i>, vol. 7, pp. 88-96, 2010. https:\/\/doi.org\/10.1021\/ct100469b<\/a>\n\n<\/li>\n
  5. J.M. BIJVOET, A.F. PEERDEMAN, and A.J. van BOMMEL, \"Determination of the Absolute Configuration of Optically Active Compounds by Means of X-Rays\", Nature<\/i>, vol. 168, pp. 271-272, 1951. https:\/\/doi.org\/10.1038\/168271a0<\/a>\n\n<\/li>\n
  6. H.S. Rzepa, and M.Y. Yi, \"An AM1 and PM3 molecular orbital and self-consistent reaction-field study of the aqueous solvation of glycine, alanine and proline in their neutral and zwitterionic forms\", Journal of the Chemical Society, Perkin Transactions 2<\/i>, pp. 531, 1991. https:\/\/doi.org\/10.1039\/p29910000531<\/a>\n\n<\/li>\n
  7. A. Banerjee, S. Datta, A. Pramanik, N. Shamala, and P. Balaram, \"Heterogeneity and Stability of Helical Conformations in Peptides:\u2009 Crystallographic and NMR Studies of a Model Heptapeptide\", Journal of the American Chemical Society<\/i>, vol. 118, pp. 9477-9483, 1996. https:\/\/doi.org\/10.1021\/ja960665u<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    Understanding why and how proteins fold continues to be a grand challenge in science. I have described how Wrinch in 1936 made a bold proposal for the mechanism, which however flew in the face of much of then known chemistry. Linus Pauling took most of the credit (and a Nobel prize) when in a famous […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"activitypub_content_warning":"","activitypub_content_visibility":"","activitypub_max_image_attachments":5,"activitypub_interaction_policy_quote":"anyone","activitypub_status":"","footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[4],"tags":[497,509,575,17,431,24,508,504,2651,507,249,498,510,373,572],"ppma_author":[2661],"class_list":["post-3802","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","tag-alpha-helix","tag-aqueous-solutions","tag-chiroptical","tag-conformational-analysis","tag-dielectric","tag-energy","tag-energy-components","tag-high-energy-species","tag-historical","tag-jack-dunitz","tag-julia-contreras-garcia","tag-protein","tag-solvation-algorithms","tag-tutorial-material","tag-watoc11"],"yoast_head":"\nWhy are \u03b1-helices in proteins mostly right handed? - Henry Rzepa's Blog<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=3802\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Why are \u03b1-helices in proteins mostly right handed? - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Understanding why and how proteins fold continues to be a grand challenge in science. 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The reaction was first introduced into the organic chemistry laboratories here at Imperial College decades ago, vanished for a short period, and has recently been reintroduced again.\u2021 The experiment is\u2026","rel":"","context":"In "reaction mechanism"","block_context":{"text":"reaction mechanism","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1086"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":14423,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14423","url_meta":{"origin":3802,"position":1},"title":"Intermolecular atom-atom bonds in crystals? The O…O case.","author":"Henry Rzepa","date":"July 25, 2015","format":false,"excerpt":"I recently followed this bloggers trail; link1 \u2192 link2 to arrive at this delightful short commentary on atom-atom bonds in crystals by Jack Dunitz. Here he discusses that age-old question (to chemists), what is a bond? Even almost 100 years after Gilbert Lewis' famous analysis, we continue to ponder this\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"OO-query","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2015\/07\/OO-query.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":16361,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=16361","url_meta":{"origin":3802,"position":2},"title":"What is the approach trajectory of enhanced (super?) nucleophiles towards a carbonyl group?","author":"Henry Rzepa","date":"May 11, 2016","format":false,"excerpt":"I have previously commented on the B\u00fcrgi\u2013Dunitz angle, this being the preferred approach trajectory of a nucleophile towards the electrophilic carbon of a carbonyl group. Some special types of nucleophile such as hydrazines (R2N-NR2) are supposed to have enhanced reactivity due to what might be described as\u00a0buttressing of adjacent lone\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":14161,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14161","url_meta":{"origin":3802,"position":3},"title":"The formation of tetrahedral intermediates.","author":"Henry Rzepa","date":"June 12, 2015","format":false,"excerpt":"In the preceding post, I discussed\u00a0the reaction between mCPBA (meta-chloroperbenzoic acid) and cyclohexanone, resulting in Baeyer-Villiger oxidation via a tetrahedral intermediate (TI). Dan Singleton, in whose group the original KIE (kinetic isotope measurements) were made, has kindly\u00a0pointed out\u00a0on this blog that his was a mixed-phase reaction, and that mechanistic comparison\u2026","rel":"","context":"In "reaction mechanism"","block_context":{"text":"reaction mechanism","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=1086"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":19983,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=19983","url_meta":{"origin":3802,"position":4},"title":"Organocatalytic cyclopropanation of an enal: (computational) mechanistic understanding.","author":"Henry Rzepa","date":"August 25, 2018","format":false,"excerpt":"Symbiosis between computation and experiment is increasingly evident in pedagogic journals such as J. Chemical Education. Thus an example of original laboratory experiments, that later became twinned with a computational counterpart. So when I spotted this recent lab experiment I felt another twinning approaching. The reaction under consideration is that\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":14016,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=14016","url_meta":{"origin":3802,"position":5},"title":"The B\u00fcrgi\u2013Dunitz angle revisited: a mystery?","author":"Henry Rzepa","date":"May 12, 2015","format":false,"excerpt":"The B\u00fcrgi\u2013Dunitz angle is one of those memes that most students of organic chemistry remember.\u00a0It hypothesizes the geometry of attack of a\u00a0nucleophile\u00a0on a\u00a0trigonal\u00a0unsaturated (sp2) carbon in a\u00a0molecule\u00a0such as\u00a0ketone, aldehyde,\u00a0ester, and\u00a0amide\u00a0carbonyl. Its value obviously depends on the exact system, but is generally taken to be in the range 105-107\u00b0. A very\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]}],"jetpack_likes_enabled":false,"authors":[{"term_id":2661,"user_id":1,"is_guest":0,"slug":"admin","display_name":"Henry Rzepa","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/3802","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3802"}],"version-history":[{"count":6,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/3802\/revisions"}],"predecessor-version":[{"id":21492,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/3802\/revisions\/21492"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3802"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3802"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3802"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=3802"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}